Impairments in language, social interaction and behavioral flexibility that together occur in young children comprise the hallmarks of autism spectrum disorder (ASD). Language, and thus autism, is a uniquely human phenotype, but studies of its neurophysiological and molecular basis require animal models. The broad long-term objective of this proposal is to develop a novel model of ASD using the zebra finch songbird. While no single model will capture all features of ASD, songbirds are one of the few in which the language subcomponent comprised by learned vocal communication can be studied. This is because songbirds, like humans and unlike traditional laboratory animals, learn their vocalizations through social interactions with conspecifics. Support for this idea comes from comparing the expression patterns of the autism susceptibility gene, contactin-associated protein-like 2 (Cntnap2) in the brains of vocal learners and non-learners. In both humans and finches, Cntnap2 is enriched in regions that are functionally specified for learned vocal communication. In contrast, transcript distribution in rodent brain shows no region-specific enrichment. As humans with CNTNAP2 mutations exhibit features of ASD and SLI, we will develop small hairpin RNA constructs that decrease Cntnap2 levels, first in cultures of zebra finch telencephalic neurons, then in ovo in the developing embryo. We will determine the effects of Cntnap2 reduction on electrophysiological and neuroanatomical properties in vitro and in vivo, and on vocal learning, other social and repetitive behaviors. Not only will this work illuminate Cntnap2's role in ASD, it will additionally provide a proof-of- principle for use of songbirds in understanding the role of other autism susceptibility genes on socially-learned vocal communication. A songbird model of ASD promises to provide critical information about cellular and circuit effects, and will be useful for screening therapeutic interventions. Our studies aim to inform novel approaches to improve social interactions, and thus the quality of life, of autistic children. PUBLIC HEALTH RELEVANCE: Children diagnosed with autism fail to develop language, have other social difficulties and overly repetitive behaviors. To understand the neural basis for these deficits, we will develop a novel model of autism using songbirds, arguably the only practical laboratory model for probing the vocal learning subcomponent of language. We will investigate the role of the autism susceptibility gene, Cntnap2, on vocal learning and other social and repetitive behaviors, with the goal of applying these findings to humans and formulating novel approaches to improve social interactions, speech learning, and the quality of life of autistic children.